Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors

Abstract

Merestinib is an oral multi-kinase inhibitor targeting a limited number of oncokinases including MET, AXL, RON and MKNK1/2. Here, we report that merestinib inhibits neurotrophic receptor tyrosine kinases NTRK1/2/3 which are oncogenic drivers in tumors bearing NTRK fusion resulting from chromosomal rearrangements. Merestinib is shown to be a type II NTRK1 kinase inhibitor as determined by x-ray crystallography. In KM-12 cells harboring TPM3-NTRK1 fusion, merestinib exhibits potent p-NTRK1 inhibition in vitro by western blot and elicits an anti-proliferative response in two- and three-dimensional growth. Merestinib treatment demonstrated profound tumor growth inhibition in in vivo cancer models harboring either a TPM3-NTRK1 or an ETV6-NTRK3 gene fusion. To recapitulate resistance observed from type I NTRK kinase inhibitors entrectinib and larotrectinib, we generated NIH-3T3 cells exogenously expressing TPM3-NTRK1 wild-type, or acquired mutations G595R and G667C in vitro and in vivo. Merestinib blocks tumor growth of both wild-type and mutant G667C TPM3-NTRK1 expressing NIH-3T3 cell-derived tumors. These preclinical data support the clinical evaluation of merestinib, a type II NTRK kinase inhibitor (NCT02920996), both in treatment naïve patients and in patients progressed on type I NTRK kinase inhibitors with acquired secondary G667C mutation in NTRK fusion bearing tumors.

First-in-Human Phase I Study of Merestinib, an Oral Multikinase Inhibitor, in Patients with Advanced Cancer

“…Although designed to be an inhibitor of MET, merestinib also inhibits the receptor tyrosine kinases MST1R, AXL, ROS1, PDGFRA, FLT3, TEK, DDR1, DDR2, MERTK, TYR03, TRKA, TRKB, and TRKC , as well as the serine/threonine kinases MKNK1 and MKNK2 . This property may explain the occasional observed responses in the few patients with tumor regression in our study.…”

“…Merestinib (LY2801653), developed initially to target the MET kinase, is an oral kinase inhibitor with antitumor proliferative and antiangiogenic activity in MET‐amplified and MET autocrine xenograft tumor models . Merestinib is also active against other receptor tyrosine kinases (MST1R [RON], AXL, ROS1, PDGFRA, FLT3, TEK, DDR1, DDR2, MERTK, TYR03, TRKA, TRKB, and TRKC) and serine/threonine kinases (MKNK1 and MKNK2) . Recent studies demonstrated merestinib inhibits MKNK1‐ and MKNK2‐induced phosphorylation of eukaryotic translation initiation factor 4E and may represent a unique approach to treatment of acute myeloid leukemia or tumors with mitogen‐activated protein kinase pathway activation .…”

Revisiting NTRKs as an emerging oncogene in hematological malignancies

“…Apart from the aforementioned inhibitors, many others have been validated in solid tumors bearing NTRK fusions or mutations. These include cabozantinib [109], foretinib [109], merestinib [110], and nintedanib [109] among others. Moreover, IGF1R/IR pathway inhibitors, in particular, have shown to be effective at blocking EN activity by initiating a process that results in the ubiquitylation and proteasomal degradation of the fusion protein itself [96].…”

Mammary analogue secretory carcinoma of the salivary gland with NTRK fusions: new approaches for diagnostics and targeted therapy (review)

“…Развитие лекарственной устойчивости описано и при применении других ИТК. Для преодоления резистентности в настоящее время проводятся клинические исследования I-II фазы ИТК 2-го поколения, таких как селитректиниб (selitrectinib, Loxo-195), репотректиниб (repotrectinib; TPX-0005 в исследовании TRIDENT-1), мерестиниб (merestinib, LY2801653) [24]. [25] с разрешения авторов) Fig.…”